Cystic fibrosis-related diabetes is caused by islet loss and inflammation
Cystic fibrosis-related diabetes is caused by islet loss and inflammation
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DOI：
10.1172/jci.insight.98240
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发表时间：
2018-04-19
期刊：
影响因子：
8
通讯作者：
Powers, Alvin C.
中科院分区：
文献类型：
--
作者：
Hart, Nathaniel J.;Aramandla, Radhika;Powers, Alvin C.
囊性纤维化相关（CF 相关）糖尿病 (CFRD) 是一种日益常见且具有破坏性的 CF 合并症，影响约 35% 的成人 CF 患者。然而，CFRD 的根本原因尚不清楚。在这里，我们使用 β 细胞 CFTR 缺失的小鼠模型以及正常和 CF 人胰腺和胰岛检查囊性纤维化跨膜电导调节器 (CFTR) 胰岛表达以及 CFTR 是否参与胰岛内分泌细胞功能。从小鼠β细胞中特异性删除CFTR并不影响β细胞功能。在人胰岛中，CFTR mRNA 表达量最低，未检测到 CFTR 蛋白和电活动。分离的 CF/CFRD 胰岛表现出适当的胰岛素和胰高血糖素分泌，关键胰岛调节转录本几乎没有变化。此外，CF 供体中大约 65% 的 β 细胞面积丢失，再加上胰腺重塑和胰岛的免疫浸润。这些结果表明，CFRD 是由复杂多效性疾病背景下的 β 细胞丢失和胰岛内炎症引起的，而不是由 CFTR 突变引起的内在胰岛功能障碍引起的。
Cystic fibrosis-related (CF-related) diabetes (CFRD) is an increasingly common and devastating comorbidity of CF, affecting approximately 35% of adults with CF. However, the underlying causes of CFRD are unclear. Here, we examined cystic fibrosis transmembrane conductance regulator (CFTR) islet expression and whether the CFTR participates in islet endocrine cell function using murine models of beta cell CFTR deletion and normal and CF human pancreas and islets. Specific deletion of CFTR from murine beta cells did not affect beta cell function. In human islets, CFTR mRNA was minimally expressed, and CFTR protein and electrical activity were not detected. Isolated CF/CFRD islets demonstrated appropriate insulin and glucagon secretion, with few changes in key islet-regulatory transcripts. Furthermore, approximately 65% of beta cell area was lost in CF donors, compounded by pancreatic remodeling and immune infiltration of the islet. These results indicate that CFRD is caused by beta cell loss and intraislet inflammation in the setting of a complex pleiotropic disease and not by intrinsic islet dysfunction from CFTR mutation.